Zika virus (ZIKV), a mosquito-borne flavivirus, is now reported to be circulating in 26 countries and territories in Latin America and the Caribbean. While infected individuals can often be asymptomatic or have only mild symptoms, emerging evidence starts to link ZIKV infection to fetal and newborn microcephaly and serious neurological complications, such as Guillain-Barr syndrome. The WHO declared a Public Health Emergency of International Concern on Feb 1 of 2016. Though the structure, tropism and pathogenesis of ZIKV are largely unknown, several recent studies started to shed lights on the etiology of the virus. Indeed, recent studies published by Ming and colleagues demonstrated that ZIKV specifically infect human neuronal progenitor cells. The next important step is to elucidate the molecular mechanism of ZIKV-host interactions. It has been well documented that once a virus enters the host cell, it hijacks the cellular machineries, mainly via direct, physical contacts with host proteins. Therefore, construction of a ZIKV-host protein-protein interaction network will greatly facilitate our understanding of the molecular mechanism of ZIKV life cycle. In addition, comparison of the ZIKV- host interactions with dengue virus (DENV)-host interactions will provide us important clues to identify novel therapeutic targets. Specifically, we plan to: 1) Construct ZIKV and DENV-host protein-protein interaction networks; 2) Predict which host factor(s) plays an important role in ZIKV-host interactions; and 3) Validate newly identified ZIKV-host PPIs using cell-based approaches. The success of this project will provide us a global PPI network between ZIKV and human proteome. The comparison between ZIKV-host and DENV-host PPI networks will improve the likelihood for us to identify important host factors and/or pathways that are commonly exploited by the flavivirus. We believe that PPI datasets will serve as an important stepping stone towards identifying novel drug targets that will greatly facilitate development of novel therapeutics and vaccines.